First-in-human dose-escalation study of the selective EGFR/HER2 exon 20 inhibitor PFL-721 in patients with locally advanced or metastatic NSCLC.

8619 Background: PFL-721 is a highly selective, orally bioavailable tyrosine kinase inhibitor (TKI) targeting activating EGFR & ERBB2 exon 20 (ex20) mutations while sparing wild-type (WT) EGFR. Preclinical studies demonstrate potent inhibition of diverse ex20 variants, >20-fold selectivity over WT EGFR, and robust antitumor activity in xenograft models. Methods: PFL-721 is investigated in an ongoing phase I study in patients (pts) with advanced NSCLC and EGFR/ERBB2 ex20 alterations (Clinical trial identifier: NCT06043817). PFL-721 is administered once daily (QD) in continuous 28-day cycles. Assessments included adverse events (AEs), dose-limiting toxicities (DLTs), PK, and antitumor activity by RECIST v1.1. Key eligibility criteria included locally documented EGFR/ERBB2 ex20 alterations on solid or liquid tumor biopsy, ECOG 0–1, and adequate organ function. Molecular responses were based on EGFR/ERBB2 ex20 alterations variant allele frequency decrease in ctDNA. Results: A total of 45 pts were dosed , with a median age of 63 years. Pts had received a median of 3 prior treatment lines. Thirty-one pts had EGFR ex20 alterations, 13 had ERBB2 ex20 insertion mutations, and one had both. Dose levels evaluated were 30, 60, 120, 240, 360, 480, and 600 mg QD. Dose escalation was completed with the identification of the maximum tolerated dose at 480 mg. AEs were reported in 43 pts (96%), including gastro-intestinal AEs in 39 pts (87%). Commonly observed grade ≥3 AEs included diarrhea (n=10/45, 22% of pts ), hypokalemia (n=4/45 , 9%), and increased blood creatinine (n=3/45, 7%). One grade 3 rash was observed. Six DLT events occurred in 39 evaluable pts, including grade 3 diarrhea (at 360 mg QD, n=2; 480 mg QD, n=1, 600 mg QD, n=1), grade 3 fatigue (600 mg QD, n=1), and grade 4 hypokalemia (600 mg QD, n=1). PK analyses showed dose-proportional exposure and achievement of plasma concentrations predicted to be effective based on preclinical models, at doses of ≥240 mg QD. Among efficacy population (n=42), partial responses (PRs) were observed in 15 / 28 pts at doses of ≥360 mg QD . The overall response and disease control rates at doses ≥360 mg QD were 54% (95%CI [33. 9-72.5]) and 79% (95%CI [59.0-97.7]), respectively. Among 25 evaluable pts, molecular responses (ctDNA decrease >50%) were observed in 12 at doses ≥120 mg. Conclusions: In this dose escalation study, class-effect local gastrointestinal AEs were observed in nearly all pts while the frequency of systemic skin toxicity was low, in line with the selectivity of the molecule for mutant EGFR. Antitumor activity was reported in 54% of pts at doses ≥360 mg QD in a heavily pretreated population, including with prior EGFR/ERBB2 ex20 TKI. Consistent with tumor shrinkage, ctDNA clearance was observed in 48% of evaluable pts. The randomized dose-optimization part is ongoing, with three dose regimens: 360 mg QD, 480 mg QD, and 240 mg BID. Clinical trial information: NCT06043817 .